Classical Galactosaemia Clinical Trial
Official title:
Galactosaemia, a Modifiable Multi-system Glycosylation Disorder?
Galactosaemia is an inherited condition caused by a lack of an enzyme (catalyst) which
normally breaks down galactose (the sugar found in milk products). This affects 1:19,000
births annually in Ireland (the highest incidence worldwide) and is screened for by the
National Newborn Screening Programme. When an affected infant is diagnosed, galactose is
immediately restricted from the diet. This prevents often fatal liver disease and other
immediate complications. However, despite early treatment the majority of affected patients
go on to develop long-term complications such as intellectual impairment, neurological
complications, speech difficulties and infertility in females. The underlying mechanisms for
these complications are unclear. The investigators have shown in detailed biochemical and
gene analysis studies that major abnormalities affecting the function of complex molecules
in the body, particularly glycoproteins, (consisting of sugar chains attached to proteins)
persist in treated individuals which may lead to disturbances of the body's intrinsic
cellular machinery and relate to the complications seen.
In this research the investigators expand on from their earlier studies to see if they can
identify biomarkers and parts of the galactose/glycosylation pathways which could be
modified or changed with new treatments to improve outcomes for this condition (i.e., IgG N
glycans).
In more detail, the investigators test the use of the most abundant glycoprotein in human
plasma (IgG) as an improved clinical test for monitoring the galactose control needed in
patients and also to see if some patients (including children aged 5-12 yrs) might have a
better predicted outcome with moderate increases of galactose in the diet. The investigators
believe that these studies greatly improve the understanding of Galactosaemia with a view to
improving current treatment options and future outcomes.
Classical Galactosaemia is an inherited disorder of galactose metabolism caused by profound
deficiency of galactose-1-phosphate uridyltransferase (GALT: EC 2.7.712). This results in a
systemic accumulation of toxic galactose intermediates and a decrease in the level of
UDP-galactose, a required sugar for glycosylation. Galactosaemia has a relatively high
incidence in Ireland, (1:19,000 births) presenting a particular public health problem. The
neonatal life-threatening phenotype (liver disease, coagulopathy and sepsis) is rescued by
restriction of dietary galactose. However, outcomes of treatment are disappointing beyond
the neonatal period (even after successful newborn screening, early treatment and long term
compliance). The majority of Irish patients harbour the severe Q188R Galt mutation.
56.5% of Irish patients ≥ 6yrs have IQs ≤ 79; and 91.2% of Irish female patients ≥ 13yrs
have Premature Ovarian Insufficiency (POI). Unfortunately, the basic pathophysiology of this
condition remains enigmatic with limited treatment approaches.
In their earlier work, the investigators reported very considerable variation in patient
outcomes, even among siblings. The investigators have proposed that these differences are
determined by variation in galactose accessory pathways (beyond the GALT deficiency). This
may result in variable galactose tolerance in patients with linked variation in
glycosylation pathways which could allow for enhanced UDP-galactose bioavailability
essential for glycosylation. In their previous and current work the investigators have
identified ongoing dysregulation of glycoprotein formation and expression of genes involved
in glycan biosynthesis and cell signalling pathways in treated Galactosaemia patients.
The present proposal, which builds on published previous work, enables the investigators to
establish that Galactosaemia is a modifiable, multi-systemic glycosylation defect. The
overall objectives of the work are to progress the development of biochemical markers (IgG
N-glycan analysis) as prognostic indices for potentially modifiable relevant pathways. The
investigators consider how the phenotype could be relaxed in some patients with Classical
Galactosaemia, initially by studies of modification of exogenous galactose requirements to
identify if the ongoing glycan processing defects identified may be improved reflecting
accessory pathways of galactose disposal.
Study Aim: Expand previous and published work using IgG N-glycan analysis to examine the
glycosylation status of treated adult Galactosaemia patients in a larger study and develop
this test as a reliable diagnostic tool. The investigators also carry out a pilot study to
examine the effects of diet relaxation in paediatric patients (5-12 yrs) aiming to determine
optimum galactose intake levels for this cohort with the hope of preventing long-term
complications later in life. The investigators propose that this research offers new
insights into the ongoing pathophysiology of this rare disorder with the possibility of
developing new treatment targets, which over time could be cost-effective by preventing
major disability.
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Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment